Immune checkpoint blockade in locally advanced rectal cancer with deficient DNA mismatch repair: retrospective multicenter experience.

[BACKGROUND] Prospective, single-institution studies in deficient DNA mismatch repair (dMMR) locally advanced rectal cancer (LARC) have shown high rates of complete clinical response (cCR) to neoadjuvant immune checkpoint inhibitor (ICI) monotherapy.

[PATIENTS AND METHODS] We conducted a multisite, retrospective, and cross-sectional analysis of dMMR LARC patients (N = 21) treated at four academic medical centers. The objective response rate (ORR) after neoadjuvant ICI treatment was assessed by sequential pelvic magnetic resonance imaging scans and flexible sigmoidoscopy. Clinical variables analyzed included tumor-node-metastasis stage (I-III), rectal tumor location (proximal, mid, and distal), and sporadic dMMR or Lynch syndrome.

[RESULTS] The median age of patients was 46 years; 71% were male. Tumors (N = 21) were staged as III (n = 15), II (n = 3), I (n = 2), and 1 unknown (T4NxM0). Twenty patients received anti-programmed cell death protein 1 (anti-PD-1) monotherapy; one received combined anti-PD-1 and anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) treatment. The median duration of ICI treatment was 7 months (range 2-23 months). The ORR was 85.7% [95% confidence interval (CI) 63.7% to 97.0%], which includes 11 (52.4%; 95% CI 29.8% to 74.3%) cCRs and 7 (33.3%; 95% CI 14.6% to 57.0%) partial responses. Stable disease was achieved in 1 (4.8%) patient (95% CI 0.1% to 23.8%) and progressive disease in 2 (9.5%) patients (95% CI 1.2% to 30.4%). Among 18 patients with any clinical response, the median time to best clinical response was 6 months (interquartile range 4.2-7.7 months). Salvage chemoradiation therapy and surgery were carried out in 9 of 10 patients with an incomplete clinical response. The 1- and 2-year disease-free survival rates were 100% (95% CI 85.7% to 100%) and 87% (95% CI 72% to 100%), respectively.

[CONCLUSION] Neoadjuvant ICI therapy for dMMR LARC produced cCRs in at least half of patients. These real-world data support the feasibility of nonoperative management, but the observed heterogeneity in clinical response highlights the need to optimize patient selection and monitoring strategies.