Adding Immunotherapy to Chemoradiotherapy in Rectal Cancer Shows Safety, No Efficacy Gain

The combination therapy of Yervoy (ipilimumab), an anti–CTLA-4 therapy, and Opdivo (nivolumab), an anti–PD-1 therapy, is safe and feasible, demonstrating no statistically significant increase in surgical complications or reoperation rates compared to chemoradiotherapy (CRT) alone according to phase 2 results from the Chinorec trial published in JAMA Network Open. The trial data was an important step in exploring immunotherapy for microsatellite-stable (MSS) rectal cancer, a group historically resistant to immune checkpoint inhibitors (ICIs).

ICIs have revolutionized treatment for several cancers, but their benefits in colorectal cancer have largely been confined to the 10–15% of patients with microsatellite instability (MSI). For the majority with MSS disease, ICIs alone have shown little effect. Preclinical studies suggest that radiotherapy may “prime” tumors, enhancing immunogenicity and potentially sensitizing MSS tumors to ICIs. This trial tested whether adding dual ICI to CRT could safely boost response rates in rectal cancer.

Johannes Laengle, M.D., Ph.D., from the Division of Visceral Surgery, Department of General Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria and his team hypothesized that radiotherapy can enhance tumor immunogenicity, effectively "priming" the tumor microenvironment to become more responsive to immune attack. Preclinical evidence supports promising synergy between radiation and ICIs. Furthermore, combining both nivolumab and ipilimumab inhibitors aimed for a more potent effect: CTLA-4 blockade depletes regulatory T cells and enhances T-cell priming, while PD-1 blockade reduces T-cell exhaustion. The key question the CHINOREC trial sought to answer was whether adding this dual blockade to CRT would safely enhance complete response rates.

The CHINOREC trial was a prospective, randomized, open-label, multicenter phase 2 study conducted in Austria between 2020 and 2024. 80 patients with locally advanced rectal cancer were randomized to receive either standard CRT (n=30) or CRT plus ipilimumab and nivolumab (n=50). The median age was 60 years; 61% were male. Participants either received neoadjuvant treatment with 50 Gy in 25 fractions with concurrent capecitabine or CRT plus ipilimumab (1 mg/kg, day 7) and nivolumab (3 mg/kg every 2 weeks × 3 doses starting day 14). In both groups, surgery was performed 10–12 weeks after CRT.

The primary outcome was the safety and feasibility of the combination, assessed by comparing surgical complications and reoperation rates. Safety was the priority because surgery remains the cornerstone of curative treatment, and CTLA-4 inhibitors are generally associated with increased immune-related adverse events that could complicate operations. Secondary outcomes included pathological and clinical response rates, including complete response and major pathological response.

Crucially, differences in surgical complication rates were not statistically significant between the standard CRT group and the CRT plus ICI group (77% in both arms). Reoperation rates were also comparably low (8% in CRT vs. 7% in the combination arm). The incidence of serious adverse events (SAEs) that were directly attributable to ICIs was only 6% in the combination arm, suggesting that the short-course ICI dosing schedule successfully minimized perioperative risks associated with this class of drug. From a feasibility standpoint, nearly all patients completed CRT; most in the experimental arm received all planned ICI doses. Surgery was performed in 86% of patients across both groups, with no excess perioperative mortality attributable to immunotherapy.

The key secondary outcome of complete response (clinical or pathological) did not significantly improve with the addition of dual ICIs. The complete response rate was 30% in the CRT group and 22% in the CRT plus ipilimumab and nivolumab group. Similarly, the rates of major pathological response (MPR, defined as 10% or less residual vital tumor) were nearly identical: 38% in the CRT group and 37% in the combination group. Molecular analyses showed both arms had a high prevalence of proficient mismatch repair status (MSS), confirming the trial focused on the resistant tumor subtype.

The CHINOREC trial demonstrates that adding ipilimumab and nivolumab to neoadjuvant CRT is safe and feasible, with no increase in surgical morbidity or mortality. This is a significant finding, as safety concerns have been a major barrier to integrating immunotherapy into curative-intent rectal cancer treatment.

The trial, however, did not demonstrate a substantial enhancement in full or major pathological response rates. This may be due to the small sample size, the exploratory phase 2 design, or the fact that dual ICI may not have helped unselected patients much more than CRT. Significantly, certain patients in the experimental group chose nonoperative “watch-and-wait” care following suspected clinical full responses, underscoring the evolving significance of organ-preserving therapies.

The study also emphasizes the necessity for biomarker-driven patient selection. MSI tumors respond well to ICIs, but MSS tumors may need more priming techniques, better sequencing, or new combinations.