Dostarlimab may eliminate the need for surgery in early-stage dMMR tumours

PD-1 blockade with dostarlimab may eliminate the need for surgery in patients with early-stage mismatch repair–deficient (dMMR) solid tumours amenable to curative intent surgery, a phase II trial has shown.

dMMR tumours are highly sensitive to immune checkpoint blockade. [Med 2024;5:839-841] “Complete elimination of dMMR primary tumours with PD-1 blockade alone in patients with rectal cancer has led to the question of whether this approach could be extended beyond rectal cancer to all early-stage dMMR solid tumours, regardless of tumour site,” wrote the researchers. [N Engl J Med 2025;doi:10.1056/NEJMoa2404512; AACR 2025, abstract CT003]

The researchers therefore enrolled 117 patients (median age, 57.0 years; male, 51 percent) with stage I, II, or III dMMR solid tumours at any site that were amenable to curative-intent surgery into the current study. All patients were treated with neoadjuvant dostarlimab for 6 months and monitored for treatment response, disease progression, or recurrence. Patients were categorized into two cohorts: those with rectal cancer and those with nonrectal solid tumours. Patients with a clinical complete response (CR) could elect to proceed with nonoperative management, while those with residual disease were to undergo surgery.

All patients with rectal cancer (49 of 49) and 65 percent of patients (35 of 54) with nonrectal solid tumours achieved clinical CR. Of the 103 patients in both cohorts who experienced CR, 82 chose to skip surgery. In all patients with clinical CR, organs were preserved without additional therapy.

A major concern with neoadjuvant therapy is that the “window of opportunity” for resection may lapse if the tumour grows and spreads to the point where it becomes no longer amenable to curative-intent surgery. “Notably, the option for curative resection was not compromised during or after [dostarlimab] treatment in any of the patients,” highlighted the researchers.

Disease recurrence developed in only five patients across both cohorts. One patient had tumour regrowth at the primary tumour site, and four patients had recurrence solely in lymph nodes.

In the overall population, 92 percent of patients were still disease-free at 2 years. At the time of reporting, four patients’ CRs had lasted for 5 years.

The use of dostarlimab for 6 months was associated with few adverse events (AEs). The majority of patients had reversible grade 1 or 2 AEs (60 percent) or had no AEs at all (35 percent).

“Data from this study, which were obtained from a small group of patients with stage I, II, or III dMMR solid tumours, showed that neoadjuvant PD-1 blockade enabled a nonoperative management strategy in a high proportion of patients,” noted the researchers. “The potential effect is substantial, given that 2–3 percent of all early-stage solid tumours are dMMR.”

“These findings are very important for [these] patients because it is likely that they do not need surgery or radiation if they are treated first with immunotherapy for a sufficient amount of time,” commented lead author, Dr Andrea Cercek of the Memorial Sloan Kettering Cancer Center. “Surgical resection can be complicated and risky, especially in organs such as the stomach, pancreas, or rectum, so this approach can lead to organ preservation, which offers a better quality of life and a potential survival benefit.”