Colon to Rectum
N Engl J Med. 2024;390(21):1949–58
Neoadjuvant immunotherapy in locally advanced mismatch repair-deficient colon cancer
Background: Mismatch repair-deficient (dMMR) tumors can be found in 10–15% of patients with non-metastatic colon cancer. In these patients, the efficacy of chemotherapy is limited. The use of neoadjuvant immunotherapy has shown promising results, but data from studies of this approach are limited. Methods: The authors conducted a phase 2 study in which patients with non-metastatic, locally advanced, previously untreated dMMR colon cancer were treated with neoadjuvant nivolumab plus ipilimumab. The 2 primary end points were safety, defined by timely surgery (i.e., ≤ 2-week delay of planned surgery owing to treatment-related toxic events), and 3-year disease-free survival. Secondary end points included pathological response and results of genomic analyses. Results: Of 115 enrolled patients, 113 (98%; 97.5% confidence interval [CI]: 93–100) underwent timely surgery; 2 patients had surgery delayed by more than 2 weeks. Grade 3 or 4 immune-related adverse events occurred in 5 patients (4%), and none of the patients discontinued treatment because of adverse events. Among the 111 patients included in the efficacy analysis, a pathological response was observed in 109 (98%; 95% CI: 94–100), including 105 (95%) with a major pathological response (defined as ≤ 10% residual viable tumor) and 75 (68%) with a pathological complete response (0% residual viable tumor). With a median follow-up of 26 months (range, 9–65), no patients have had recurrence of disease.
Conclusions: In patients with locally advanced mismatch repair-deficient colon cancer, neoadjuvant nivolumab plus ipilimumab had an acceptable safety profile and led to a pathological response in a high proportion of patients.
Prof. Dr. Michael Quante
Head of Gastrointestinal Oncology, Department of Internal Medicine II, University Medical Center Freiburg (Germany)
The critical role of MSI status testing in patients receiving neoadjuvant immunotherapy
Immune checkpoint inhibitors have shown significant efficacy in patients with mismatch repair-deficient (dMMR) metastatic colorectal cancers, resulting in improved progression-free survival. dMMR tumors are found in approximately 8–15% of patients with non-metastatic colon cancer. In this subset, chemotherapy has limited efficacy. Even with adjuvant chemotherapy, patients with dMMR tumors, especially those classified as stage T4 or with lymph node involvement, have a high risk of recurrence.
The phase 2 NICHE-2 study, conducted by the Netherlands Cancer Institute, evaluated the safety and efficacy of neoadjuvant immunotherapy in patients with locally advanced dMMR colon cancer. Participants received a single dose of the CTLA4 inhibitor ipilimumab and 2 doses of the PD1 inhibitor nivolumab, followed by surgery within 4 weeks. Of the 115 patients enrolled, 98% (97.5% confidence interval [CI]: 93–100) underwent surgery as planned. In the efficacy analysis of 111 patients, 98% (95% CI: 94–100) showed a pathological response, with 95% achieving a major pathological response and 68% achieving a complete pathological response. No patients discontinued treatment due to adverse events, and no disease recurrence was observed after a median follow-up of 26 months.
While these findings suggest that neoadjuvant nivolumab and ipilimumab may offer a new treatment approach for locally advanced dMMR colon cancer, they do not yet support this approach as the standard of care for all patients with early-stage dMMR colon cancer. Surgical resection alone is curative for most stage II dMMR cases, and adjuvant therapy is primarily recommended for stage III disease. Staging of dMMR colon cancer is challenging due to the frequent presence of enlarged lymph nodes caused by immune infiltration, leading to the possibility of overtreatment. Additionally, while the incidence of grade 3 or 4 adverse events from immune checkpoint blockade in this study was only 4%, 11% of patients developed long-term endocrine dysfunction.
A randomized trial comparing neoadjuvant immunotherapy plus surgery with surgery alone or surgery followed by adjuvant immunotherapy in node-positive disease would help clarify the risk-benefit profile. The key takeaway remains the importance of testing for MMR/MSI status in all patients with colon cancer in order to guide appropriate treatment.