Immunotherapy before surgery cleared tumours in a 56-patient colon cancer trial

For colon cancer that can be removed with surgery, the standard path is an operation followed, in some cases, by chemotherapy. A small phase 2 trial published in Nature Medicine on 2 November asked a different question: what happens if you give a short course of immunotherapy first, before the tumour is ever cut out [s1]?

What the drugs are

The trial, called UNICORN, tested two immune checkpoint inhibitors [s1]. Botensilimab, abbreviated BOT, is described as a multifunctional, Fc-enhanced antibody that blocks CTLA-4, a brake on immune cells [s1]. Balstilimab, abbreviated BAL, blocks PD-1, a second brake [s1]. The idea behind giving them before surgery is that the tumour is still in place to act as a target, so the immune response the drugs unleash has something to recognise and attack.

A central distinction in colon cancer shaped the design. Some tumours are mismatch-repair deficient (dMMR), meaning they have lost the machinery that fixes DNA copying errors; these accumulate mutations and tend to respond to checkpoint inhibitors [s1]. Most colon cancers are mismatch-repair proficient (pMMR) and have long been considered resistant to the first generation of these drugs [s1]. UNICORN set out to test both groups [s1]. The pMMR arm is the harder test, because it is both the more common form and the one where checkpoint inhibitors have historically failed; the Fc-enhancement of botensilimab is meant to recruit additional immune cells in exactly such tumours [s1].

How the trial was built

UNICORN is a window-of-opportunity platform trial registered as NCT05845450 [s1][s2]. It enrolled 56 patients with resectable, locally advanced colon cancer [s1]. Twenty-eight had pMMR tumours and were assigned in sequence to a botensilimab-alone cohort (n=14) and a botensilimab-plus-balstilimab cohort (n=14) [s1]. The other 28 patients, with dMMR tumours, followed the same sequential allocation into the two cohorts [s1].

The primary endpoint was the rate of pathological major response, judged by a central review of the removed tumour and defined as 10% or less residual viable tumour tissue [s1]. In plainer terms, after the short pre-surgery course, how much living cancer was left in the specimen the surgeon took out. A long list of secondary measures tracked safety, quality of life, and biological signals including circulating tumour DNA [s1].

What it found

The primary endpoint was met in every cohort except pMMR tumours given botensilimab alone [s1]. The pathological major response rate was 0% (95% confidence interval 0–23.2%) in the pMMR botensilimab-alone cohort, 36% (95% CI 12.8–64.9%) in the pMMR combination cohort, 36% (95% CI 12.8–64.9%) in the dMMR botensilimab-alone cohort, and 100% (95% CI 76.8–100%) in the dMMR combination cohort [s1].

The combination in dMMR tumours is the headline: a central read found no more than 10% living cancer in every patient. The combination also worked in a share of the proficient tumours long thought to be beyond the reach of these drugs, while botensilimab alone did not clear the bar in that group [s1]. The authors report that clearance of circulating tumour DNA — fragments of tumour genetic material in the blood — before surgery tracked with pathological response and with an absence of recurrence by the data cutoff, a hint that a simple blood test might one day flag who is responding [s1].

Side effects followed the pattern of immune activation. Immune-related adverse events occurred in 8 of 28 patients (29%) given botensilimab alone and 15 of 28 (54%) given the combination, most commonly a flu-like syndrome and diarrhoea [s1].

What is, and is not, established

UNICORN supports a specific conclusion: a short preoperative course of botensilimab plus balstilimab produced pathological responses in both dMMR and pMMR resectable colon cancer, and the authors frame the combination as a promising way to extend checkpoint-inhibitor benefit into early-stage disease [s1].

The limits are large. This is a phase 2 trial of 56 people, split into cohorts of 14 [s1]. Patients were enrolled in sequence rather than randomly assigned, so the cohorts are not balanced comparison groups [s1]. The endpoint is pathological response in the removed tumour — a biological signal measured at surgery, not whether patients lived longer or avoided recurrence over years, which the trial was not built or sized to settle [s1]. Adding balstilimab raised the rate of immune side effects [s1]. And both drugs are investigational in this setting; these results describe a trial, not an approved treatment [s1].

Red flags: anyone on a checkpoint inhibitor who develops persistent diarrhoea, breathlessness, a new rash, or unusual fatigue should contact their oncology team promptly, as immune-related reactions can affect the bowel, lungs, and other organs. This article describes early research and is not medical advice. Decisions about treating colon cancer before surgery are for patients and their treating oncologists.