Findings from a small study support a non-surgical and tumour-agnostic approach with immunotherapy, but further research is needed
Findings from a phase 2 study published in The New England Journal of Medicine show that neoadjuvant PD-1 blockade with dostarlimab led to a sustained clinical complete response in a substantial proportion of patients with early-stage mismatch repair-deficient (dMMR) solid tumours (N Engl J Med. 2025 Apr 27).
Immune-checkpoint inhibitors have demonstrated clinical efficacy in colorectal cancers, and rectal cancer specifically, when used in the neoadjuvant setting in previous research (N Engl J Med. 2024 Jun 6;390(21):1949-1958; N Engl J Med. 2022 Jun 23;386(25):2363-2376). The trial involved a total of 117 patients with various stage I–III dMMR tumors including esophagogastric, hepatobiliary, genitourinary, and gynaecologic tumours, who were eligible for curative-intent surgery. Study participants were divided into two cohorts (rectal and non-rectal tumours) and treated with dostarlimab for six months (500 mg every three weeks), and then monitored for response, progression, or recurrence.
In cohort 1, all patients (n=49) with rectal malignancies completed treatment and had a clinical complete response, and 76% (n=37) had a sustained clinical complete response at 12 months after completion of treatment. In cohort 2, 65% of patients with different non-rectal tumours who completed treatment had a clinical complete response, and 61% elected to proceed with nonoperative management. Among the 103 patients who completed treatment across both cohorts, 82% had a clinical complete response, and 80% did not undergo surgery.
“The study has important implications. For rectal cancer, where standard care with radiotherapy and surgery have significant long-term morbidity, these findings support large-scale studies of “definitive” immunotherapy for localised tumours”, explains Dr Philippe Cassier of Centre Léon Bérard in Lyon, France. “For non-rectal cancer, the sample size of the study precludes definitive conclusions. Nevertheless, a 65% of complete clinical response with immune-checkpoint inhibition is higher than the rate most standard of care therapy can achieve in some solid tumours. Discrepancy in the clinical complete response rates across different cancers indicates that separate studies should be done for each tumour type to address potential differences in sensitivity to immunotherapy.”
While the study highlights the potential of neoadjuvant immunotherapy for dMMR cancers, questions remain about its broader applicability according to Cassier. “Conducted at high-volume, expert centers, the findings may be difficult to generalise. One key challenge is the assessment of complete response using imaging, which can be technically complex and variable across institutions.” Other pending issues include the optimal duration of immunotherapy, the best timing to assess response to treatment and the most appropriate surveillance strategies. “Also, in some settings surgery may offer a better therapeutic index, particularly for early-stage (T1/T2N0) tumours of the colon or small bowel amenable to minimally invasive resection,” he concludes.
