Immunotherapy replaces surgery for early-stage DMMR cancers in the Landmark trial

Immunotherapy replaces surgery for early-stage DMMR cancers in the Landmark trial

A phase 2 study shows that PD-1 blockade can safely replace surgery for many early-stage DMMR cancers, offering patients a chance at a cure without invasive surgery.

In a recently published study inThe New England Journal of MedicineA group of investigators evaluated whether neoadjuvant programmed cell death 1 (PD-1) blockade can achieve organ preservation in patients with early-stage mismatch repair deficient (DMMR) solid tumors across multiple tumor types.

background

Imagine being able to beat cancer without surgery. Approximately 2-3% of all solid-stage tumors exhibit DMMR, a genetic defect that makes tumors highly sensitive to immunotherapy. In metastatic settings, DMMR tumors respond remarkably to PD-1 blockade regardless of tumor origin. Inspired by the success in DMMR rectal cancer, the researchers asked: Could surgery be avoided in other early-stage DMMR tumors? If effective, this strategy could spare patients invasive procedures and long-term disability. However, the durability and universality of this approach remain uncertain. The researchers also noted that while organ preservation can have serious life-altering effects for cancers where surgery is particularly likely to have serious life-changing effects, such as rectal, esophageal or bladder cancers, different tumor types respond differently to immunotherapy. Therefore, further large-scale, long-term studies are essential to validate these results.

About the study

This phase 2 study enrolled patients with newly diagnosed stage I, II, or III solid tumors who exhibited DMMR. Screening took place at Memorial Sloan Kettering Cancer Center, Hartford Healthcare and Baptist Health Miami Cancer Institute. Eligibility required loss of expression of mismatch repair proteins, specifically Mutl homolog 1 (MLH1), Muts homolog 2 (MSH2), Muts homolog 6 (MSH6), or postmeiotic segregation increasing 2 (PMS2), which was confirmed by immunohistochemical staining.

Patients received dostarlimab, a PD-1 blocking agent, administered intravenously at a dose of 500 mg 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 tumors. Clinical responses were assessed eight weeks after therapy using tumor-specific imaging and endoscopy. Patients with a clinical complete response could opt for non-surgical treatment, while patients with residual disease were recommended 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. Surveillance included circulating tumor deoxyribonucleic acid (DNA) as a biomarker. All patients provided written informed consent, and an institutional review board approved the protocol. It is important to note that this was a one group study without a randomized control arm. The authors emphasized that for some tumor types, particularly those that are not highly disabling to surgery (such as colon cancer), randomized trials may be needed before practice changes are widespread.

Study results

Of 124 enrolled patients, 117 were included after excluding patients with disease progression or withdrawal. Among the 103 who completed treatment, 49 had rectal cancer and 54 had non-rectal tumors. 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 elected nonoperative treatment. At 12 months post-treatment, 37 patients maintained their response and met the study's efficacy criteria. The results in rectal cancer were particularly impressive and were 100% complete in treated patients. In cohort 2 (non-rectal tumors), 35 of 54 patients (65%) achieved clinical complete response and 33 elected nonoperative management. However, the authors emphasized that the analyzes on non-rectal tumor types were exploratory and the median follow-up for recurrences in this group was shorter (14.9 months), warranting longer follow-up before definitive conclusions can be drawn. No patient with a complete response had tumor progression or became surgically unresectable during or after treatment.

Overall, 84 of 103 patients (82%) in both cohorts had clinical complete responses, and 82 patients (80%) avoided surgery completely. Recurrence was rare, occurring in only five patients - four with lymph node recurrences and one with local regrowth at the primary tumor site. The two-year recurrence-free survival rate was an impressive 92%, with a median follow-up of 20 months.

Adverse events were manageable, with 60% of patients experiencing mild adverse events (Grade 1 or 2), including fatigue, rash, or pruritus. Serious events were rare and no deaths were reported.

Circulating tumor DNA analysis was highly correlated with treatment outcomes. Patients with clinical complete responses demonstrated rapid clearance of circulating tumor DNA, while patients with residual disease or relapse demonstrated sustained positivity. This highlights circulating tumor DNA as a potential real-time biomarker for treatment monitoring.

Genomic analyzes confirmed high similarity between baseline and post-treatment tumor samples, indicating that most clinical incomplete responses were not due to the development of new tumors. Furthermore, resumption of PD-1 blockade in patients who developed recurrence resulted in disease regression in several cases, suggesting that immune immunity was preserved.

Dr. Andrea Cercek reflected the broader clinical significance, stating: "This is very exciting and shows that a wide range of tumors with this genetic mutation, called MMRD, can be treated with immunotherapy, replacing surgery and radiation and giving patients a better quality of life." (Note: This is a paraphrase summarizing the results and not a direct quote from the NEJM article.)

This study demonstrated that neoadjuvant dostarlimab could preserve organs later without compromising curative options. Notably, prostate and gastroesophageal cancers were less likely to achieve complete responses, likely due to biological differences in the tumor microenvironment. The authors suggest that further research may clarify whether longer treatment durations or combination immunotherapy could improve responses in these tumor types.

Conclusions

In conclusion, this study shows that neoadjuvant PD-1 blockade with dostarlimab enables organ preservation in a high proportion of patients with early-stage DMMR tumors. Most patients achieved durable disease control without undergoing surgery, improving quality of life and preserving organ function. Recurrence of disease was rare and often manageable with withdrawal. However, the authors caution that these results are based on exploratory analyzes with limited follow-up, particularly for non-rectal tumors, and larger long-term studies, including randomized trials for specific cancer types, are needed to fully confirm the safety and effectiveness of this organ preparation approach. These results could significantly change the treatment paradigm for early-stage DMMR cancers.

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