AACR 2025 | Nonoperative management of early-stage mismatch repair-deficient cancers
Neoadjuvant checkpoint blockade of locally advanced mismatch repair deficient cancers could eliminate the need for surgical resection, regardless of tumor type.
Preliminary results from a Phase II trial investigating the efficacy of PD-1 blockade with Jemperli® (dostarlimab) demonstrated complete tumor clearance and the chance for organ preservation in patients with locally advanced mismatch repair-deficient (dMMR) cancers. The data, presented at the AACR Annual Meeting (25–30 April, IL, USA), provides a basis for treatment approaches and clinical trials in the neoadjuvant setting.
Immune checkpoint blockade inhibitors, such as dostarlimab, are approved as a neoadjuvant treatment for many cancers, including metastatic or unresectable dMMR solid cancers. Previous results from this trial have demonstrated that neoadjuvant checkpoint blockade or locally advanced dMMR rectal cancers results in high rates of clinical complete response, eliminating the need for surgery.
While dMMR occurs most frequently in rectal and colon cancers, it can also occur broadly across other solid tumors. Whether or not the positive results of neoadjuvant checkpoint blockade can extend to non-rectal cancers in a tumor agnostic manner, remains to be determined.
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Results from the trial update included 103 patients, with both rectal and non-rectal cancer. Those eligible for the trial – patients with early-stage dMMR solid tumors eligible for curative intent surgery – were enrolled in a 6-month study of neoadjuvant treatment with dostalimab.
The study was split into two cohorts; the first included 49 rectal cancer patients, and the second included 54 non-rectal cancer patients. This included patients with gastroesophageal, gynecological, hepatobiliary and genitourinary cancers. Both cohorts shared the primary endpoint of clinical complete response after dostalimab, and exploratory endpoints involving circulating tumor DNA (ctDNA).
Patients who received a clinical complete response in either cohort could elect non-surgical management. In cohort one, all 49 patients who completed dostalimab treatment had a clinical complete response and opted to proceed with nonoperative management. In cohort two, 35 non-rectal cancer patients (65%) had a clinical complete response after treatment, with 33 opting for nonoperative management.
Looking at the exploratory endpoints, 95% of patients had detectable ctDNA prior to treatment. Following treatment, lower levels of ctDNA were associated with a higher likelihood of clinical complete response. The authors also noted that some patients had excellent tumor downstaging; however, after 6 months did not experience complete response, suggesting more treatment would be beneficial.
The authors also provided an update on recurrence-free survival in the rectal cancer cohort, demonstrating that 92% of patients remained disease-free at 2 years.
“These findings are very important for patients with early-stage dMMR tumors because it’s likely they do not need surgery or radiation if they are treated first with immunotherapy for a sufficient amount of time,” commented lead author Andrea Cercek.
“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 as well as a potential survival benefit.”
Overall, these results demonstrate treatment approaches for dMMR cancers that preserve organs and improve survivorship, regardless of tumor type.