Is a Single Preoperative Immunotherapy Dose Enough in dMMR Colon Cancer?

Are Treatment Strategies for Colon Cancer Changing?

Although surgery is considered the most important step in colon cancer treatment, immunotherapies have brought a major revolution in recent years. They can be particularly effective in colon cancers with deficient DNA mismatch repair (dMMR).

Results presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (#ASCOGI25) from the RESET-C trial showed that just one course of neoadjuvant pembrolizumab, an anti-PD-1 immunotherapy, produced a high rate of pathological complete response (pCR) in early-stage dMMR colon cancer. But is this single-dose treatment enough to delay surgery or make it unnecessary?

Findings from the RESET-C Trial

In this phase 2, single-arm trial, 85 patients diagnosed with stage I-III dMMR colon cancer received a single dose of pembrolizumab before surgery (4 mg/kg, up to 400 mg). Of these patients, 84 underwent surgery within 3-5 weeks; only one patient, with stage I disease, declined surgery.

The key findings were as follows:

• Overall, 44% (37 patients) achieved a pathological complete response (pCR).

• 57% (48 patients) had a major pathological response.

• The pCR rate was 61% (20/33 patients) in stage I-II disease and 33% (17/51 patients) in stage III disease.

• No disease recurrence was detected during 1 year of follow-up.

• Grade 3 adverse events occurred in 7 of the 85 patients (8%); 3 were immune-related adverse events (2 cases of hepatitis and 1 of colitis).

• No grade 4 or 5 immune-related adverse events were observed.

• Two patients older than 80 died within 30 days after surgery, but these deaths were not attributed to immunotherapy.

Why Was a Single Dose Chosen? Could More Doses Have Made a Difference?

RESET-C used only a single dose of pembrolizumab to examine the effect of immunotherapy in early-stage disease and assess its potential to delay surgery. While most previous trials had examined longer or combination immunotherapy regimens, this trial aimed for a maximum response with minimal treatment.

However, given the response rates achieved with a single dose, uncertainty remains about how these rates might have differed with 2-4 doses. Further studies are needed to determine whether additional doses would provide more benefit and improve effectiveness in stage III disease. Future trials comparing immunotherapy at different doses and durations may provide clearer answers.

The Trial's Importance and Future Implications

Dr. Camilla Qvortrup of Copenhagen University Hospital, Denmark, who presented the trial, emphasized the "very impressive" responses produced by neoadjuvant immunotherapy in localized dMMR colon cancer. However, she added that the optimal treatment duration and combinations still need to be established.

These findings once again demonstrate the strong effect of immunotherapy on dMMR tumors. However, there is not yet enough evidence to determine whether a single dose of pembrolizumab is sufficient to make surgery unnecessary.

Conclusion: Will Surgery Remain the Standard?

RESET-C is an important step that could open the way to new approaches in colon cancer treatment. Complete responses in 61% of patients after a single pembrolizumab dose suggest the possibility of delaying surgery or treating without surgery, particularly in early-stage disease. However, more research is needed on the long-term effectiveness of immunotherapy, recurrence rates and whether it can replace surgery.

The lower response rates in stage III disease and the continued recommendation of surgery as standard treatment underline the need for further research. Larger studies are expected to clarify the future balance between immunotherapy and surgery.