Immune checkpoint inhibitors with neoadjuvant chemoradiotherapy in proficient MMR rectal cancer: systematic review and meta-analysis

BACKGROUND: To evaluate the efficacy and safety of neoadjuvant chemoradiotherapy plus immune checkpoint inhibitors (CRT-ICI) for mismatch repair proficient (pMMR) locally advanced rectal cancer (LARC). METHODS: Five databases were systematically searched. Pooled pathological complete response (pCR) and composite clinical response (CR) and grade 3-4 neoadjuvant-related adverse events (AEs), surgical AEs, and immune-related AEs (ir-AEs) were calculated, and comparative results (CRT-ICI vs. CRT alone) were conducted on randomized clinical trials (RCTs) via risk ratios (RRs). Also, subgroup analyses were conducted in pMMR-exclusive cohorts for all available endpoints. RESULTS: Eighteen studies (1,619 patients) were included. The pooled pCR rate was 41% (95% CI: 36-47%) overall and in the pMMR-exclusive group (95% CI: 35-48%). Composite CR rates were 49% (95%CI: 38-60%) overall and 54% (95%CI: 41-66%) in pMMR cohorts. Analysis of comparative RCTs showed CRT-ICI significantly improved both pCR (RR 1.7, 95%CI:1.38-2.09) and CR rates (RR 1.76, 95%CI:1.43-2.17) compared to CRT alone. The pMMR-exclusive group confirmed a significant CR (RR 1.76, 95%CI:1.3-2.37, p < 0.01) and pCR (RR 1.66, 95%CI:1.15-2.4; p < 0.01) benefit. Grade 3-4 neoadjuvant-related AEs occurred in 23% of patients, with a significant increase over CRT alone (RR 1.26, 95%CI:1.01-1.57). Surgical complications (6% overall; 4% in the pMMR-exclusive group) and ir-AEs (4% overall; 3% in the pMMR-exclusive group) were infrequent. A subgroup analysis of RCTs showed that short-course ICI containing regimen (SCRT + ICI) significantly improved pCR (RR 1.90, 95%CI: 1.36-2.65) and CR (RR 1.84, 95%CI: 1.37-2.47) over SCRT alone. However, long-course regimen (LCRT + ICI) did not show a benefit over LCRT alone (pCR: RR 1.31, 95%CI 0.94-1.81, CR: RR 1.17, 95%CI 0.53-2.59). Additionally, SCRT + ICI led to higher pooled pCR/CR rates than LCRT + ICI (CR: 59% vs. 36%, p = 0.031; pCR: 51% vs. 33%, p < 0.0001). CONCLUSION: In pMMR LARC, our results suggested that neoadjuvant CRT-ICI was associated with higher pCR/CR rates than CRT alone based on the analysis of available trials. This effect, however, appears confined to SCRT-ICI, with no corresponding gain seen in LCRT-ICI. Although treatment‑related toxicity is increased, severe immune‑related and surgical adverse events are infrequent. These findings suggest that selective use of CRT‑ICI may be considered, particularly when downstaging or organ preservation is a goal, but confirmatory trials and continued longitudinal follow‑up are warranted to assess response durability, survival benefits, and late toxicity.