Neoadjuvant immune checkpoint inhibitor (ICI) therapy demonstrates notable activity in non-metastatic deficient mismatch repair/microsatellite instability-high (dMMR/MSI) colorectal cancer (CRC), with high response rates and favourable clinical outcomes, as shown in the ongoing ambispective international observational study AGEO-NEO-MSI.
In a cohort of 316 dMMR/MSI CRC patients treated with neoadjuvant ICIs, the primary endpoint of complete response (CR) rate (ie, clinical or pathological CR) among those who were managed without surgery was 67 percent. [ESMO GI 2026, abstract 3RO]
Among patients who underwent resection, 34 percent achieved clinical CR, 66 percent achieved pathologic CR, and 11 percent achieved major pathologic response.
Clinical CR strongly predicted pathologic CR or major pathologic response, with a positive predictive value of 93 percent to 96 percent, reported lead researcher Dr Annalice Gandini from the Centre de Recherche des Cordeliers in Paris, France.
However, the sensitivity was only around 20 percent, which means that clinical response assessment alone may not be able to identify many patients with pathologic CR, Gandini added.
Event-free survival and safety
Over a median follow-up of 16 months, event-free survival rates were 92.3 percent at 1 year and 86.3 percent at 2 years. Rates were numerically higher among patients who received combination ICIs (91.2 percent at both time points) than among those who received single-agent ICI (92.1 percent at 1 year and 85.4 percent at 2 years).
Gandini pointed out that the high 2-year event-free survival rate of 86 percent associated with neoadjuvant ICIs in real-world practice fell slightly short of the 100 percent rate reported in some clinical trials.
Immune-related adverse events (irAEs) occurred in 35.1 percent of patients overall, including grade ≥3 irAEs in 6.3 percent. The most common irAEs were skin toxicity (12 percent), thyroiditis (10.4 percent), rheumatologic events (7.3 percent), colitis (4.8 percent), and hepatitis (3.5 percent).
Of note, grade ≥3 irAEs occurred more frequently among patients who received doublet vs single-agent ICI (12.5 percent vs 4.5 percent; p=0.024).
The rate of toxicity-related discontinuation was 8.9 percent. There was one case of treatment-related death (0.3 percent) reported in a patient who received doublet ICIs.
Predictors of CR
In an exploratory analysis, a short-course doublet-ICI strategy of <1 month was associated a more than twofold higher odds of achieving clinical or pathologic CR compared with long-course single-agent ICI therapy (76 percent vs 59.8 percent; adjusted odds ratio, 2.13, 95 percent confidence interval, 1.05–4.66; p=0.045).
However, higher irAEs rate was also associated with an increased likelihood of CR but only among patients who received single-agent ICI (p=0.003 for interaction).
AGEO-NEO-MSI supports the implementation of adjuvant ICI therapy for treating dMMR/MSI CRC in clinical practice, according to Gandini. “Combination strategies and irAEs shape response, highlighting the need for treatment optimization.”
AGEO-NEO-MSI
AGEO-NEO-MSI is being conducted in more than 30 international centres across Austria, Belgium, France, Italy, Spain, and the US. The analysis included 316 patients (median age 68 years, 51 percent female, 94 percent had ECOG PS 0–1) with dMMR/MSI CRC and no distant metastases, of whom 24 received single-agent ICI and 72 received doublet ICI in the neoadjuvant setting with a median duration of 83.5 days.
At baseline, most patients had stage 3 disease (75 percent), tumours located in the right colon (62 percent), and resectable primary tumour (73 percent).
More patients who received single-agent vs doublet ICI were managed nonoperatively (46 percent vs 12 percent). Resection was performed in 54 percent of patients who received single-agent ICI and in 88 percent of those who received doublet ICI.