Neoadjuvant chemoradiotherapy plus sintilimab in pMMR/MSS rectal cancer patients with PD-L1 TPS ≥ 1% or CPS ≥ 1: an open-label, prospective, phase II study

Abstract

This phase II clinical trial aimed to evaluate the efficacy and safety of neoadjuvant long-course chemoradiotherapy combined with sintilimab in mismatch repair-proficient (pMMR)/microsatellite-stable (MSS) locally advanced rectal cancer (LARC) patients with a PD-L1 tumor proportion score (TPS) ≥1% or combined positive score (CPS) ≥1. The primary endpoint was pathological complete response (pCR), and safety was assessed. This trial was registered on ClinicalTrials.gov (identifying number: NCT04833387) with the registration date of April 4, 2021. Although the target pCR rate was not fully achieved, a notable improvement was observed, with 7/20 (35.0%) patients achieving pCR in the intention-to-treat analysis. A trend toward higher pCR rates was observed in patients with PD-L1 CPS ≥ 5 than in those with CPS < 5 (50.0% vs. 27.3%, P = 0.311). Treatment-related adverse events occurred in 12 patients (60.0%), with no grade 4 events. Biomarker analysis revealed that higher CD3 (P < 0.001) and CD8 (P = 0.018) expression, along with lower TIM-3 (P = 0.017) expression in the stroma, was associated with higher pCR rates.

Fig. 1

Study the flow diagram.

Fig. 2. Tumor response of the patients assessed in this study.

A Waterfall plot of radiological change in maximum tumor diameter from baseline. B Swimmer plot of the patients receiving CRT and sintilimab in this cohort.

Fig. 3. Evolution of endoscopic and radiographic response in representative patients treated with sintilimab.

The results of T2-weighted MRI of the rectum, endoscopic evaluations, and pathological results for two representative patients pre- and post-treatment are shown. A (Patient 4) shows a stable disease on endoscopic and imaging evaluations after treatment. B (Patient 5) shows an endoscopic complete response and a near‑complete response on T2‑weighted rectal MRI after treatment. Red arrows identify the tumor at each time point.

Fig. 4. Multiplex immunohistochemistry analysis of biomarker expression.

A–D Representative SETDB1, CD3, LAG-3, CD8, IDO, B7H4, B7H3, VISTA, and TIM3 staining of pretreatment specimens of patient 11 (Response) and patient 9 (No response). Scale bars, 100 µm. E–G Box plot of CD3, CD8, and TIM3.