Preoperative Short-Course Radiotherapy Followed by Chemotherapy and PD-1 Inhibitor Administration for Locally Advanced Rectal Cancer: The Initial Results of a Randomized Phase II/III Trial (STELLAR II study).

For locally advanced rectal cancer (LARC), previous STELLAR study has shown that a new total neoadjuvant therapy (TNT) paradigm of short-course radiotherapy (SCRT) followed by chemotherapy can achieve higher complete response (CR) rate compared to standard chemoradiotherapy (CRT), meanwhile, the 3-year DFS is not inferior to CRT. Recent studies have shown that, PD-1/PD-L1 inhibitors may improve the complete response of LARC and have strong synergistic potential with radiotherapy, especially hypo-fractionated mode. Thus, the STELLAR II trial aims to investigate whether SCRT-based TNT combined with PD-1 inhibitor could further improve prognosis. The outcomes of the initial 100 enrolled patients are presented. This is a prospective, multicenter, two-arm randomized controlled, seamless phase II/III trial for pMMR/MSS LARC. Patients will receive the TNT regimen and be randomly assigned to two groups: the iTNT group and the TNT group. Patients in both groups will receive SCRT (25 Gy/5 fx) followed by 4 cycles of CAPOX or 6 cycles of mFOLFOX, with the iTNT group receiving the same chemotherapy in combination with Sintilimab. TME surgery or W&W strategy will be performed after neoadjuvant therapy and then 2 cycles of same regimen as before are recommended. The primary endpoints are the complete response (CR) rate for phase II trial and 3-year DFS for phase III trial. The initial 100 patients enrolled from 10 hospitals were analyzed for tolerability and toxicity as planned, of which 54 and 46 patients are in the iTNT and TNT groups, respectively. 75% of the patients were men and the median age was 69 years (range = 21-73). Most of them had T3-4 (97%), N1-2 (92%) and lower location (79%) tumors, with half of MRF+ (50%) and EMVI+ (51%). 2 patients withdrew before treatment. 98 patients completed SCRT, and the 4-cycle chemotherapy ± Sintilimab completion rates were 83.3% and 95.5% in the iTNT and TNT groups, respectively. In the iTNT group, 7 patients did not receive immunotherapy, 5.6%, 9.3% and 72.2% received 2, 3 and 4 cycles of PD-1 inhibitor respectively. The rates of grade 3-5 toxicities were 33.3% in the iTNT group versus 20.5% in the TNT group, and thrombocytopenia was the most common in both groups. A total of 13.5% irAEs were observed, including 3 grade 3 cases. 7 patients in each group achieved cCR and opted for W&W strategy. The pCR rates and CR rates were 40.0% (12/30) versus 18.8% (6/32) and 40.4% versus 31.0% in the iTNT and TNT groups, respectively. This trial is a head-to-head, SCRT-based study that can definitively explore the value and toxicity of PD-1 inhibitors combined with TNT for LARC. The acute toxicity was tolerable from the initial results, and the iTNT group showed a surprising CR rate to look forward to. Clinical trial information: NCT05484024. [ABSTRACT FROM AUTHOR]