A phase 2 trial shows that PD-1 blockade can safely replace surgery for many early-stage dMMR cancers, offering patients a chance at a cure without invasive operations.
Study: Nonoperative Management of Mismatch Repair–Deficient Tumors. Image Credit: Lightspring / Shutterstock
In a recent study published in The New England Journal of Medicine, a group of researchers 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 told you could beat cancer without surgery. Approximately 2-3% of all early-stage solid tumors exhibit dMMR, a genetic flaw that makes tumors highly sensitive to immunotherapy. In metastatic settings, dMMR tumors respond remarkably to PD-1 blockade, irrespective of tumor origin. Inspired by success in dMMR rectal cancer, researchers asked: could surgery also be avoided in other early-stage dMMR tumors? If effective, this strategy could spare patients invasive procedures and long-term disabilities. 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, esophageal, or bladder cancers, different tumor 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 I, II, or III solid tumors exhibiting dMMR were enrolled. Screening occurred at Memorial Sloan Kettering Cancer Center, 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 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 using tumor-specific imaging and endoscopy eight weeks post-therapy. Patients with a clinical complete response could opt for nonoperative 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 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 single-group study without a randomized control arm; the authors emphasized that for some tumor types, particularly those where surgery is not severely disabling (such as colon cancer), randomized trials may be necessary before practice changes are widely adopted.
Study results
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 nonrectal 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 chose nonoperative 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 (nonrectal tumors), 35 out of 54 patients (65%) achieved a clinical complete response, and 33 elected nonoperative management. However, the authors emphasized that analyses in nonrectal tumor 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 tumor 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 tumor 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 tumor DNA analysis strongly correlated with treatment outcomes. Patients with clinical complete responses exhibited rapid clearance of circulating tumor DNA, while those with residual disease or recurrence showed persistent positivity. This highlights circulating tumor DNA as a potential real-time biomarker for treatment monitoring.
Genomic analyses confirmed a high similarity between baseline and post-treatment tumor samples, indicating that most clinical incomplete responses were not due to the development of new tumors. 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 stated, "This is very exciting and shows that a broad range of tumors with this genetic mutation, called MMRd, can be treated with immunotherapy, replacing surgery and radiation, giving patients better quality of life." (Note: This is a paraphrase summarizing the findings and not a direct quotation from the NEJM article.)
This study demonstrated that neoadjuvant dostarlimab could preserve organs without compromising curative options later. 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
To summarize, this study shows that neoadjuvant PD-1 blockade with dostarlimab enables organ preservation in a high proportion of patients with early-stage dMMR solid tumors. Most patients achieved durable disease control without undergoing surgery, improving quality of life and preserving organ function. Disease recurrence was rare and often manageable with retreatment. However, the authors caution that, especially for nonrectal tumors, these results are based on exploratory analyses with limited follow-up, and larger, long-term studies, including randomized trials for certain cancers, are needed to fully confirm the safety and efficacy of this organ-preserving approach. These results could significantly change the treatment paradigm for early-stage dMMR cancers.
Source:
Journal reference: