Oncology · Medical Literature
Short-Course Radiotherapy-Based Total Neoadjuvant Therapy plus Tislelizumab for Locally Advanced Rectal Cancer (Neo-STAR): Early Outcomes of a Randomized Phase II Trial.
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).
Clinical relevance
Locally advanced rectal cancer (LARC) managed with short-course radiotherapy (SCRT)-based total neoadjuvant therapy (TNT) achieves pathological complete response (pCR) rates of only ~30%, leaving substantial room for improvement. This randomized phase II trial addresses whether adding the PD-1 inhibitor tislelizumab to SCRT-TNT can exploit the well-characterized immunostimulatory synergy between radiotherapy and immune checkpoint blockade to improve tumor regression in the neoadjuvant setting. Given the growing adoption of organ-preservation strategies in rectal cancer, optimizing pCR rates is of immediate clinical and surgical relevance.
Key findings
1. pCR rate was 45.3% (95% CI, 31.5%–59.8%) in the SCRT-TNT-ICI arm versus 27.6% (95% CI, 16.6%–40.8%) in the SCRT-TNT arm (OR = 2.17; 95% CI, 0.99–4.79; P = 0.052), representing a clinically meaningful but statistically borderline difference. 2. Major pathological response (tumor regression grade 0 or 1) was achieved in 50.9% (95% CI, 36.6%–65.2%) of the SCRT-TNT-ICI group versus 31.0% (95% CI, 19.5%–44.6%) in the SCRT-TNT group (OR = 2.31; 95% CI, 1.06–5.01; P = 0.033), reaching statistical significance. 3. The absolute difference in pCR rate between arms was approximately 17.7 percentage points, favoring the tislelizumab-containing regimen. 4. Of 111 patients who initiated treatment (53 SCRT-TNT-ICI; 58 SCRT-TNT), 89 proceeded to total mesorectal excision (45 vs. 44), indicating comparable surgical resection rates across arms. 5. Grade 3–4 adverse event incidence during neoadjuvant therapy was comparable between arms; anemia was the most frequent high-grade toxicity in both groups. No differential safety signal attributable to tislelizumab was identified at this early reporting. 6. Data on 3-year progression-free survival and 3-year overall survival (pre-specified secondary endpoints) are not yet mature and were not reported in this early outcomes analysis.
Practice implications
For patients with LARC (cT1-2N+M0 or cT3-4NanyM0 rectal adenocarcinoma) being considered for SCRT-based TNT, adding tislelizumab (anti-PD-1) to consolidation CAPOX chemotherapy may substantially improve rates of major pathological response and pCR without an apparent increase in high-grade toxicity, making this a biologically rational and clinically feasible intensification strategy. The statistically significant improvement in major pathological response (OR 2.31; P = 0.033) supports tislelizumab's role as a meaningful adjunct, though the borderline pCR result (P = 0.052) and the phase II, single-center design preclude immediate practice change; clinicians should consider enrolling eligible patients in confirmatory phase III trials. Immune-related adverse event monitoring protocols should be incorporated into the neoadjuvant treatment pathway, and patient selection should account for potential immunotherapy contraindications (e.g., active autoimmune disease, immunosuppressive therapy) pending further survival and safety data from ongoing follow-up.