Short-Course Radiotherapy-Based Total Neoadjuvant Therapy plus Tislelizumab for Locally Advanced Rectal Cancer (Neo-STAR): Early Outcomes of a Randomized Phase II Trial

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Abstract

Background: Short-course radiotherapy (SCRT)-based total neoadjuvant therapy (TNT) is used for locally advanced rectal cancer (LARC). However, the pathological complete response (pCR) rate still hovers around 30%. Radiotherapy and immune checkpoint inhibitors have been shown to exert synergistic anticancer effects. This phase II randomized clinical trial aimed to evaluate the efficacy and safety of SCRT followed by capecitabine plus oxaliplatin (CAPOX) and tislelizumab versus SCRT followed by CAPOX alone in LARC. Methods: Patients initially diagnosed with clinical tumor stage 1 to 2, with node involvement and no distant metastasis (cT1-2N+M0) or clinical tumor stage 3 to 4, with any node status and no distant metastasis (cT3-4NanyM0) rectal adenocarcinoma were randomly assigned to receive SCRT (25 Gy in 5 fractions [25 Gy/5F]), followed by 4 cycles of CAPOX combined with tislelizumab (SCRT-TNT-ICI) or CAPOX alone (SCRT-TNT). After total mesorectal excision, 2 cycles of postoperative chemotherapy were administered according to the patient's preference. The primary end point was the pCR rate, and secondary end points included major pathological response (tumor regression grade 0 or 1), 3-year progression-free survival, 3-year overall survival, and adverse events. Results: Between September 2021 and March 2024, 118 patients were randomized, of whom 111 started the allocated treatment, with 53 and 58 in SCRT-TNT-ICI and SCRT-TNT groups, respectively. Of those, 89 patients had surgical resection, including 45 in the SCRT-TNT-ICI group and 44 in the SCRT-TNT group. The pCR rate was 45.3% (95% confidence interval [CI], 31.5% to 59.8%) in the SCRT-TNT-ICI group compared to 27.6% (95% CI, 16.6% to 40.8%) in the SCRT-TNT group (odds ratio = 2.17; 95% CI, 0.99 to 4.79; P = 0.052). The major pathological response rates were 50.9% (95% CI, 36.6% to 65.2%) and 31.0% (95% CI, 19.5% to 44.6%), respectively (odds ratio = 2.31; 95% CI, 1.06 to 5.01; P = 0.033). During the neoadjuvant treatment period, the incidence of grade 3 to 4 adverse events was comparable between the SCRT-TNT-ICI and SCRT-TNT groups, with anemia being the most common in both groups. Conclusion: This phase II study provides preliminary evidence of promising tumor regression with SCRT-TNT combined with tislelizumab in LARC, warranting further validation in phase III trials. Trial registration: This trial was registered at clinicaltrials.gov (Identifier: NCT05086627).

Abstract as published, via PubMed.