Immunotherapy is considered a milestone in modern cancer treatment. While microsatellite-stable (MSS) forms of colorectal cancer were previously considered largely resistant to immune checkpoint inhibitors, a recent study by the Comprehensive Cancer Center (CCC) at MedUni Vienna and University Hospital Vienna shows that a combination of ipilimumab and nivolumab with chemoradiotherapy can be used safely in surgery for locally advanced rectal cancer – without increased complication rates. The results were published in the renowned journal JAMA Network Open.
“Our most important finding was that the integration of dual immunotherapy prior to surgery did not lead to an increase in surgical complications,” explain study leaders Johannes Längle and Michael Bergmann from the Department of General Surgery at MedUni Vienna. The rate of surgical complications was comparable in both groups, as was the frequency of reoperations (8% vs. 7%).
Good response rates and safety confirmed
A total of 80 patients were included in the randomized phase 2 study, 50 of whom received additional immunotherapy. In 37% of the patients who underwent surgery in this group, a so-called major pathological response (MPR) was achieved, i.e., a strong tumor response. Complete remission (clinical or pathological) was observed in 22%. Serious immune-mediated adverse events (SAEs) occurred in only 6% of patients, comparable to the control group receiving chemoradiotherapy alone (7%), but significantly less frequently than in more intensive total neoadjuvant therapy (TNT) protocols, in which severe side effects were reported in 27% to 38% of cases (i.e., PRODIGE 23, RAPIDO). Dual immunotherapy thus showed a favorable safety profile with good tolerability and no negative impact on surgical feasibility.
Prospects for tailored therapies
“These results provide a solid basis for further research into the use of dual immune checkpoint inhibition in combination with chemoradiotherapy,” emphasizes the study team from the CCC at MedUni Vienna. It is particularly relevant that initial signs of clinical activity were observed despite the microsatellite-stable (MSS) tumor type, which was previously considered resistant to immunotherapy. Larger, prospective studies with longer follow-up could clarify whether this combination offers long-term oncological benefits and which patients benefit most.
Next steps: Biomarkers and long-term outcomes
The researchers are now planning further studies to identify suitable biomarkers for response and to investigate the long-term effects on survival and quality of life. The aim is to identify at an early stage those patients who could particularly benefit from this form of therapy in the neoadjuvant setting.
Publication: JAMA Network Open
Dual immune checkpoint inhibition in combination with neoadjuvant chemoradiotherapy in rectal cancer: A randomized clinical trial.
Laengle J, Kuehrer I, Kulu A, Kabiljo J, Ammon D, Zirnbauer R, Stift A, Herbst F, Dauser D, Monschein M, Razek P, Haegele S, Biebl M, Geinitz H, Petzer AL, Hulla W, Müllauer L, Pils D, Widder J, Bittermann C, Tamandl D, Laengle F, Schmid R, Bergmann M.
JAMA Netw Open. 2025;8(8):e2527769. doi: 10.1001/jamanetworkopen.2025.27769