American researchers say their recent phase 2 trial has shown that PD-1 blockade (neoadjuvant programmed cell death 1) can safely replace surgery for many early-stage tumours, offering patients a chance at a cure without invasive operations.
The aim of their study – findings were published in The New England Journal of Medicine – was to evaluate whether PD-1 blockade can achieve organ preservation in patients with early-stage mismatch repair-deficient (dMMR) solid tumours across multiple tumour types.
Around 2%-3% of all early-stage solid tumours exhibit dMMR, a genetic flaw that makes them highly sensitive to immunotherapy. In metastatic settings, dMMR tumours respond remarkably to PD-1 blockade, irrespective of tumour origin.
Inspired by success in dMMR rectal cancer, the researchers asked: could surgery also be avoided in other early-stage dMMR tumours? If effective, this strategy could spare patients invasive procedures and long-term disabilities, reports News-Medical.net.
However, the durability and universality of this approach remain uncertain. The researchers also noted that while organ preservation is particularly compelling for cancers where surgery can have severe, life-altering effects, such as rectal, oesophageal, or bladder cancers, different tumour types may respond differently to immunotherapy. Therefore, further large-scale, long-term studies are essential to validate these findings.
About the study
In this phase 2 study, patients newly diagnosed with stage 1, 2, or 3 solid tumours exhibiting dMMR were enrolled after screening at Memorial Sloan Kettering Cancer Centre, Hartford HealthCare, and Baptist Health Miami Cancer Institute.
Eligibility required loss of mismatch repair protein expression, specifically MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), or postmeiotic segregation increased 2 (PMS2), confirmed via immunohistochemical staining.
Patients received dostarlimab, a PD-1 blocking agent, administered intravenously at a dose of 500mg every three weeks for six months (nine cycles). Participants were divided into two cohorts: one with locally advanced rectal cancer and the other with non-rectal dMMR tumours.
Clinical responses were assessed using tumour-specific imaging and endoscopy eight weeks’ post-therapy. Patients with a clinical complete response could opt for non-operative management, while those with residual disease were advised to undergo surgery.
The primary outcomes focused on sustained clinical complete responses at 12 months in patients with rectal cancer. Secondary measures included recurrence-free survival, safety assessments, and exploratory genomic analyses. Monitoring included circulating tumour Deoxyribonucleic Acid (DNA) as a biomarker.
It is important to note that this was a single-group study without a randomised control arm; the authors emphasised that for some tumour types, particularly those where surgery is not severely disabling (such as colon cancer), randomised trials may be necessary before practice changes are widely adopted.
Responses
Of 124 patients enrolled, 117 were included after excluding those with disease progression or withdrawal. Among the 103 who completed treatment, 49 had rectal cancer and 54 had non-rectal tumours. The median age was 57, with 64% showing lymph-node involvement on imaging.
In cohort 1 (rectal cancer), all 49 patients achieved a clinical complete response and chose non-operative management. At 12 months’ post-treatment, 37 patients maintained their response, meeting the study’s efficacy criteria.
The results in rectal cancer were particularly impressive, with a 100% complete response rate among treated patients. In cohort 2 (non-rectal tumours), 35 out of 54 patients (65%) achieved a clinical complete response, and 33 elected non-operative management.
However, the authors said analyses in non-rectal tumour types were exploratory, and the median follow-up for recurrence in this group was shorter (14.9 months), warranting longer observation before definitive conclusions can be drawn. No patient with a complete response experienced tumour progression or became surgically unresectable during or after treatment.
Overall, 84 of 103 patients (82%) across both cohorts had clinical complete responses, and 82 patients (80%) avoided surgery entirely. Recurrence was rare, occurring in only five patients – four with lymph node recurrences and one with local regrowth at the primary tumour site.
The two-year recurrence-free survival rate was an impressive 92%, with a median follow-up time of 20 months.
Adverse events were manageable, with 60% of patients experiencing mild (grade 1 or 2) side effects, including fatigue, rash, or pruritus. Severe events were rare, and no deaths were reported.
Circulating tumour DNA analysis strongly correlated with treatment outcomes. Patients with clinical complete responses exhibited rapid clearance of circulating tumour DNA, while those with residual disease or recurrence showed persistent positivity. This highlights circulating tumour DNA as a potential real-time biomarker for treatment monitoring.
Genomic analyses confirmed a high similarity between baseline and post-treatment tumour samples, indicating that most clinical incomplete responses were not due to the development of new tumours.
Moreover, among patients who developed recurrence, resuming PD-1 blockade led to disease regression in several cases, suggesting that immune sensitivity was preserved.
Reflecting the broader clinical significance, Dr Andrea Cercek said, “This is very exciting and shows that a broad range of tumours with this genetic mutation, called MMRd, can be treated with immunotherapy, replacing surgery and radiation, giving patients better quality of life.”
The study demonstrated that neoadjuvant dostarlimab could preserve organs without compromising curative options later. Notably, prostate and gastro-oesophageal cancers were less likely to achieve complete responses, probably due to biological differences in the tumour microenvironment.
The authors suggest that further research may clarify whether longer treatment durations or combination immunotherapy could improve responses in these tumour types.
Study details
Non-operative Management of Mismatch Repair–Deficient Tumours
Andrea Cercek, Michael Foote, Benoit Rousseau et al.
Published in New England Journal of Medicine on 27 April 2025
Abstract
Background
Among patients with mismatch repair–deficient (dMMR), locally advanced rectal cancer, neoadjuvant checkpoint blockade eliminated the need for surgery in a high proportion of patients. Whether this approach can be extended to all early-stage dMMR solid tumours, regardless of tumour site, is unknown.
Methods
We conducted a phase 2 study in which patients with stage I, II, or III dMMR solid tumours that were amenable to curative-intent surgery were treated with neoadjuvant dostarlimab, a programmed cell death 1 (PD-1) blocking agent, for 6 months. The response to treatment was assessed in two cohorts: patients in cohort 1 had dMMR, locally advanced rectal cancer, and patients in cohort 2 had dMMR non-rectal solid tumours. Patients with a clinical complete response could elect to proceed with non-operative management; those with residual disease were to undergo resection. In this analysis, the primary end point, assessed in cohort 1, was a sustained clinical complete response at 12 months. Recurrence-free survival and safety were evaluated.
Results
A total of 117 patients were included in the analysis. In cohort 1, all 49 patients who completed treatment had a clinical complete response and elected to proceed with non-operative management. A total of 37 patients had a sustained clinical complete response at 12 months, a finding that met the criterion for efficacy. In cohort 2, a total of 35 of 54 patients who completed treatment had a clinical complete response, and 33 elected to proceed with non-operative management. Among the 103 patients who completed treatment across both cohorts, 84 had a clinical complete response, and 82 did not undergo surgery. Among the 117 total patients, recurrence-free survival at 2 years was 92% (95% confidence interval, 86 to 99); the median follow-up for recurrence was 20.0 months (range, 0 to 60.8). The majority of patients (95%) had reversible, grade 1 or 2 adverse events (60%) or had no adverse events (35%). The option for curative resection was not compromised during or after treatment in any of the patients.
Conclusions
Among patients with early-stage dMMR solid tumours that were amenable to curative-intent surgery, neoadjuvant PD-1 blockade led to organ preservation in a high proportion of patients.
NEJM article – Non-operative Management of Mismatch Repair–Deficient Tumours (Open access)
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