Non-Operative Treatment for CRC May Include Observation After Complete Response

CHICAGO — Patients who skipped maintenance therapy after a complete response to upfront treatment with a PD-1 inhibitor lived just as long as those who had 3 years of maintenance, data from a cohort study that compared nonsurgical colorectal cancer (CRC) options showed.

After more than 3 years of follow-up, patients who entered surveillance had a disease-free survival (DFS) of 96.4% versus 98.2% for patients who continued the PD-1 inhibitor. Every patient in the observation group was alive at 3 years, as were 98.4% of the patients who received maintenance pembrolizumab (Keytruda).

Patients who received maintenance therapy had a dramatically higher rate of immune-related adverse events (irAEs) during follow-up after clinical complete response (cCR), reported Xiaohang Gao, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China, at the American Society of Clinical Oncology meeting.

“PD-1 inhibitor therapy induced cCR in 60% of patients with [deficient mismatch repair/microsatellite-high, dMMR/MSI-H] colorectal cancer, supporting non-operative management as a feasible organ-preservation strategy,” she said. “After cCR, observation achieved comparable survival to maintenance with markedly less toxicity. These findings support treatment discontinuation after cCR with close surveillance, particularly during the first 2 years, pending prospective randomized validation.”

Multiple prior studies set the stage for non-operative management of colorectal cancer, said invited discussant Filippo Pietrantonio, MD, of the National Cancer Institute in Milan, Italy. Various studies showed that key determinants of organ preservation include longer immunotherapy duration, the addition of CTLA-4 inhibition to PD-1, and reserving the strategy for patients with earlier-stage disease (II vs III).

Pietrantonio acknowledged that the study reported by Gao, “despite some intrinsic limitations,” showed that observation after cCR “was not associated with a clear loss in terms of disease-free survival, potentially reducing toxicity and cost.”

However, the study left several questions unanswered, including the optimal duration of immunotherapy, the methodology used to assess cCR, the evolving role of circulating tumor DNA in refining organ preservation strategies, and the optimal approach to observation.

Non-operative management has had a “practice-changing” impact on management of rectal cancer and has been incorporated into all major clinical guidelines, despite a lack of randomized clinical trials, Pietrantonio continued. With respect to non-operative management for dMMR/MSI-H colon cancer, “randomized trials may still be needed to balance immune-related adverse events, quality of life, and cost effectiveness of surveillance compared to surgery. Non-operative management should probably be conducted within the framework of clinical trials.”

An accumulation of evidence has shown that treatment with immune checkpoint inhibitors can enable organ preservation in dMMR/MSI-H CRC, said Gao. However, evidence from prospective studies is lacking to provide guidance about the need for continued treatment in patients who attain cCR.

To address the issue, investigators at five hospitals in China prospectively followed 318 patients with dMMR/MSI-H CRC treated with pembrolizumab during 2018-2025. Of those, 195 attained a cCR with a PD-1 inhibitor. After excluding patients who did not achieve cCR and those who chose to have surgery, 129 patients in CR began observation or 3 years of maintenance therapy.

The study population comprised 58 patients with rectal cancer, 61 with colon cancer, and 10 with multiple CRC primaries. In all cases, cCR was determined by endoscopy and imaging studies, and 80 patients had confirmatory biopsies. Confirmation of dMMR/MSI-H status was by immunohistochemistry, PCR, and next-generation sequencing. The primary endpoint was DFS from the time of cCR.

The study population had a median age of 48 years and men accounted for about 60% of the patients. About 90% had clinical stage I-III disease, 10% had clinical M1 disease, half had clinical N2 disease, and about half had clinical T4 disease.

Gao said 70% of the patients achieved cCR after eight or fewer cycles of therapy, and 94% achieved cCR within 16 cycles.

The trial met the primary endpoint of DFS after 3 years, as neither DFS (the primary endpoint) nor OS differed significantly between the two groups.

Overall, the two groups had similar rates of toxicity including irAE rates of 62.1% in the observation group and 66.7% in the maintenance group. However, the irAE burden increased substantially in the maintenance group post-cCR, as rates of new-onset or worsening irAEs were 30.2% vs 1.5% in the observation group (P<0.001). Grade ≥3 irAEs occurred in 4.8% of the maintenance group versus 0% in the observation group. The most common irAEs were thyroid dysfunction, transaminase elevation, and rash/pruritus.

Gao acknowledged several limitations of the study: its non-randomized design, low rates of oncologic events in both groups, potential toxicity selection bias from longer follow-up in the maintenance group, and heterogeneity in the PD-1 inhibitor agents and regimens.